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A newly synthetized series of N -phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone ( 5d ), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone ( 5i ), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone ( 5k ) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone ( 6a ) showed anti- C. albicans SC5314 activity, where 5d displayed MIC T = 16 µg/mL (%R = 100) and a weak anti-proliferative activity against the clinical strains: C. albicans resistant to azoles (Itr and Flu) and C. glabrata . Derivatives 5k and 6a displayed MIC P = 16 µg/mL and %R = 64.2 ± 10.6, %R = 88.0 ± 9.7, respectively, against the C. albicans isolate. Derivative 5i was the most active against C. glabrata (%R = 53.0 ± 3.5 at 16 µg/mL). Benzoxazoles displayed no MIC against C. glabrata . Benzoxazoles showed a pleiotropic action mode: ( 1 ) the total sterols content was perturbed; ( 2 ) 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4-dichlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichlorophenyl)ethanol ( 8h - i ) at the lowest fungistatic conc. inhibited the efflux of the Rho123 tracker during the membrane transport process; ( 3 ) mitochondrial respiration was affected/inhibited by the benzoxazoles: 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-chlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanol 8c - d and 8i . Benzoxazoles showed comparable activity to commercially available azoles due to ( 1 ) the interaction with exogenous ergosterol, ( 2 ) endogenous ergosterol synthesis blocking as well as ( 3 ) membrane permeabilizing properties typical of AmB. Benzoxazoles display a broad spectrum of anti- Candida activity and action mode towards the membrane without cross-resistance with AmB; furthermore, they are safe to mammals.